tbuckley/cabot-search huggingface dataset:
Assessment of the utilization of immunotherapy in Sub-Saharan Africa.
Authors: Elizabeth Oluwagbemisola Olatunji, Saloni Patel, Katy Graef, Abba Aji Mallum, Chinelo Adaobi Chigbo, Elizabeth M. Jaffee, Wil Ngwa
Journal: Journal of Clinical Oncology (2023)

e18578 Background: The Lancet Oncology Commission for sub-Saharan Africa predicts that cancer deaths will double from 520,158 per year to more than 1 million by the year 2030. These striking figures indicate a need to urgently evaluate cancer treatment infrastructure and resources in the region. Studies have found immunotherapy to be effective for the treatment of advanced-stage cancer, which almost 70% of patients in SSA present with. Despite immunotherapy’s significant curative potential, its utilization in SSA is not well documented. The purpose of this study was to evaluate the landscape of immunotherapy in SSA. Methods: A Qualtrics survey assessing the utilization and existing infrastructure and training for safe immunotherapy administration was developed and distributed online to SSA oncology networks including that of the HypoAfrica clinical trial. The target population for the survey was healthcare providers in SSA serving patients with cancer. Descriptive statistics methods were used to analyze the data. Results: 288 responses were collected from 29 countries in SSA. Clinical and medical oncologists made up 23% of respondents and nurses made up 24%. 45% of respondents were familiar with immunotherapy. 11% indicated they were adequately trained to administer it. Of these (n = 32), 53% indicated also being trained to manage immune related adverse events related to immunotherapy administration. 29% of all survey respondents indicated that their clinic has easy access to cancer immunotherapy and 45% indicated that their clinic currently practices immunotherapy. Of clinics that practiced immunotherapy (n = 129), 12% used genomic sequencing to assess tumor mutational burden, and 43% assessed patient expression of pathologic biomarker PD-L1 prior to administration. The most common types of immunotherapies used were monoclonal antibodies (44%) and checkpoint inhibitors (17%). Conclusions: Less than half of surveyed clinics currently utilize immunotherapy, and even fewer employ biologic tools to predict immunotherapy response prior to administration, which threatens the safety and efficacy of its use. Additional training for management of immunotherapy-related adverse effects is needed. Laboratory techniques to identify patients best suited for immunotherapy, and incorporation of immunotherapy training into continuous medical education may be prerequisites for wider, effective adoption of this technique in SSA.
Personalized precision combination therapies based on potential actionability and coalterations and therapeutic opportunities for CDK12-mutated prostate cancer.
Authors: Hong Zheng Li, Haitao Wang
Journal: Journal of Clinical Oncology (2023)

e17068 Background: Translational studies have reported that CDK12 aberrations in metastatic castration-resistant prostate cancer (mCRPC) are related to homologous recombination (HR) deficiency and focal tandem duplications(FTDs), characterized by gene fusions and fusion-induced neoantigens (FINAs). In prostate cancer,CDK12 aberrations as a biomarker have been reported associated with poor prognosis, whether hormonal and taxane therapies as well as to PARP inhibitors. Herein, we aimed to molecularly, pathologically, and clinically characterize CDK12-aberrant mCRPC. Methods: Clinical data and molecular analyses are collected from the mCRPC patients treated in our center. Thirty-two patients with prostate cancer underwent soft tissue biopsy or sufficient ctDNA(Circulating Tumor DNA) for NGS and confirmed the CDK12 aberrations. Twenty-eight patients had advanced to the stage of mCRPC, and twenty-seven of them had exhausted standard treatment.All of the twenty-seven patients consented to the individualized therapiees based on NGS.PSA50 response rate and progression-free survival(PFS) are used to describe clinical features and outcomes to various individualized therapies, including sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) and PD-1/PD-L1 inhibitors monotherapy or combined with other off-label drugs. Results: Of the 32 patients with CDK12-aberrant prostate cancer, 19(59.4%) had detected biallelic CDK12 alterations. At diagnosis,17 (68%) patients' PSA≥100ng (only 26 patients retained the PSA data), 27 (93.1%) had Gleason grade group 4-5(only 29 patients retained the pathology),16(51.6%) had lymph node metastasis, 16(51.6%) had bone metastasis.13 patients received PARPi combine NHT(Novel hormone therapy) or not after NHT therapy resistance,only 1 patient PSA response reached PSA50.9 patients received PARPi combine temozolomide,2 reached PSA50,1 patient's liver metastases were significantly reduced ang reached PR.In that five patients,4 of 5 were monotherapied by PARPi.21 patients accepted PD-1/PD-L1 combined with PARPi or other off-label drugs based on the NGS or not.Four patients accepted immune monotherapy,only 1 reached PSA50. In the remaining 17 combined treatment patients, PSA50 responses were noted in 23.5%. What is noteworthy is that,4 of 16 happened HPD(hyperprogressive disease) with clinical manifestations such as rapid increase of PSA and significant decrease of ECOG score. Conclusions: CDK12-aberrant mCRPC is an aggressive subtype and have worse prognosis to PARPi. PARPi combine with temozolomide may be a effective therapeutic schedule. Along with NGS development,more therapeutic drugs are available to us to benefits for patients.But immunotherapy is questionable to CDK12-aberrant mCRPC because of the lower response rate and higher risk of HPD.
Comparison of characteristics and prognostic impact of <i>FUS-ERG</i> and <i>AML1-MTG16</i> fusion genes in adult AML patients: A retrospective study from 1988 to 2022 with a medical database.
Authors: Ziyue Zhou, Yile Zhou, Yiyi Yao, Liping Mao, Yi Zhang, Qing Hong, Nanfang Zhuo, Peifeng Pan, Hongyan Tong, Jie Jin, Huafeng Wang
Journal: Journal of Clinical Oncology (2023)

7042 Background: AML1-MTG16 and FUS-ERG are two rare fusion genes in acute myeloid leukemia (AML). Their clinical characteristics and factors influencing prognosis have been summarized in a cohort of pediatric patients, but no systematic review is approached in adult. Methods: We retrospectively analyzed the clinical data of adult AML patients with AML1-MTG16 or FUS-ERG fusion genes, who were reported on Mitelman Database, PubMed and China national knowledge infrastructure (CNKI) from 1988 to 2022 or have received treatment in the First Affiliated Hospital, Zhejiang University School of Medical, and compared them with patients with RUNX1-RUNX1T1, exploring their clinical features and prognosis. Results: 314 patients were totally included for analysis. In comparison of RUNX1-RUNX1T1 group (n = 209), FUS-ERG-positive patients (n = 108) significantly exhibited a younger onset age (34.5y vs. 41y), higher WBC count (16.7 ×10 9 /L vs. 10.4×10 9 /L), higher recurrence rate (61.8% vs. 30.4%), and a worse response to chemotherapy (complete remission rate: 71.6% vs. 91.8%), while patients with AML1-MTG16 (n = 24) presented primarily as the secondary AML (83.3%) with a significantly elder age (56y vs. 41y). The FUS-ERG patients had a worse median overall survival (OS) of 13 months (95%CI: 11.6-14.4, P &lt; 0.01) and a worse median disease free survival (DFS) of 7.5 months (95%CI: 6.5-8.5, P &lt; 0.05) than control group, which also occurred in those had AML1-MTG16 gene with a median OS of 18.5 months (95%CI: 12.4-24.6, P &lt; 0.01) and a median DFS of 14 months (95%CI: 3.7-24.3, P = 0.10). As shown in the table below, CR after induction chemotherapy, hematopoietic stem cell transplantation (HSCT), trisomy, monosomy and age of patients were associated with the prognosis of FUS-ERG group. Unlike pediatric patients, the adult AML1-MTG16 patients did not perform a better outcome (OS: HR = 0.90, P = 0.83; DFS: HR = 0.54, P = 0.34) in contrast with FUS-ERG patients. Conclusions: The retrospective study summarized the clinical characteristics of AML1-MTG16 and FUS-ERG, identifying their distinctions on multiple aspects such as prior disease, recurrence rate, response to chemotherapy and cytogenetics. AML1-MTG16 exhibited extremely bad prognosis like FUS-ERG in adult population, which varied from the results in pediatric cohort. Several factors including age, CR after induction chemotherapy, HSCT, trisomy and monosomy were relevant to the prognosis of FUS-ERG. [Table: see text]
Pathologic exploration of neuroendocrine differentiation in carcinomas.
Authors: Yaru Wen, Susheng Shi
Journal: Journal of Clinical Oncology (2023)

e16238 Background: Tumor with neuroendocrine differentiation (NED) has been verified in non-neuroendocrine organ adenocarcinomas. However, the incidence of NED in various studies varies greatly due to the different selection and criteria of NED markers. Further analysis of large clinical samples is still needed to reveal its biological characteristics and clarify the diagnosis and treatment of NED. Methods: From January 2017 to June 2018，a total of 450 histopathological samples were collected and analyzed retrospectively from patients with multiple malignant cancers, including gastric cancer (GC), colorectal cancer (CRC), lung cancer, breast cancer and prostate cancer treated in Cancer Hospital, Chinese Academy of Medical Sciences. Immunohistochemical staining for NED markers such as synaptophysin (Syn), chromogranin A (ChrA), and neural cell adhesion molecule (CD56) were performed to explore the incidence of different cancer types. Furthermore, NED or non-NED patients were evaluated comparatively in terms of pathological characteristics and prognosis. Results: Up to February 6, 2023, 129 CRC and GC samples were measured. 9 (15.3%) of 59 CRC patients were positive for NED markers, including 7 cases of Syn (+), 6 cases of ChrA (+) and 2 cases of CD56 (+). Moreover, 4 (6.8%) of 59 patients were positive for at least 2 NED markers in CRC. 18 (52.9%) of 34 gastric signer ring cell carcinoma patients were positive for NED markers, including 15 cases of Syn (+) and 14 cases of ChrA (+). Meanwhile, 10 (27.8%) of 36 gastric tubular adenocarcinoma patients were positive for NED markers, including 6 cases of Syn (+) and 10 cases of ChrA (+). Particularly, 17 (24.3%) (11/6, signer ring cell carcinoma/ tubular adenocarcinoma) of 70 GC patients were positive for at least two NED markers. Conclusions: NED is widely present in colorectal cancer and gastric cancer, especially in gastric signer ring cell carcinoma. The encouraging outcomes of the NED prevalence rate may shed light on the individualized treatments for patients with carcinomas. Further explorations are needed in the following research. [Table: see text]
Final results from phase I study of PSCA-targeted chimeric antigen receptor (CAR) T cells in patients with metastatic castration resistant prostate cancer (mCRPC).
Authors: Tanya B. Dorff, Suzette Blanchard, Hripsime Martirosyan, Lauren Adkins, Gaurav Dhapola, Stephanie Shishido, Jamie R Wagner, Tracey Stiller, Massimo D'Apuzzo, Peter Kuhn, Stephen J. Forman, Saul Priceman
Journal: Journal of Clinical Oncology (2023)

5019 Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of mCRPC. Prostate Stem Cell Antigen (PSCA) is highly expressed on the surface membrane in mCRPC and with limited expression on normal tissues. We are completing a phase I study of PSCA-targeted 4-1BB-co-stimulated CAR T cell therapy in mCRPC. Methods: CAR T cells were manufactured at City of Hope’s cGMP facility. Patients (pts) were required to have disease progression after at least 1 androgen receptor targeted therapy but there was no limit on other prior treatments. The primary objective was to define the dose limiting toxicities (DLT) as well as to describe preliminary bioactivity and activity. CAR T persistence and cytokine levels were evaluated by flow cytometry and Luminex. Circulating tumor cells (CTC) were measured by an unselected assay (Kuhn). Results: 14 pts were treated, median age 69, median baseline PSA 88. 12(86%) had previously been treated with chemotherapy; 9 received two taxanes and 3 docetaxel only. 79% of screened pts had PSCA expression &gt;2+ in &gt;80% of cancer cells. Two of 6 pts encountered DLT (grade 3 cystitis) at 100M + lymphodepletion (LD) chemotherapy. The protocol was amended to reduce the LD dose to 300 mg/m2 cyclophosphamide D1-3. No DLTs occurred in 5 pts treated in the modified LD 100M cohort. Cytokine release syndrome (CRS), best response by RECIST, CAR T cell expansion and persistence are presented by dose level in the table. CAR T expansion was greater with LD than without. PSA declines were seen, as well as radiographic improvement, though RECIST response was limited to stable disease (SD) by concurrent bone metastases. Cytokine peaks were higher in patients with anti-tumor effect noted. CTC decreases in both marrow and peripheral blood were seen, associated with PSA declines. Conclusions: PSCA-CAR T cells have anti-cancer activity in mCRPC with DLT of cystitis. LD was required for greater expansion and activity; lower dose LD improved toxicity without clear negative impact on expansion. Clinical trial information: NCT03873805 . [Table: see text]
Safety and efficacy profile of a very low dose of MC-1-50 for treatment of r/r NHL.
Authors: Shiqi Li, Zhi Yang, Lin Liu, Zhongtao Yuan, Yingzi Zhang, Le Luo, Lihua Zhang, Yingnian Chen, Qianzhen Zhang, Junjie Shen, Yunyan Li, Linling Wang, Meiling Wang, Wei Zhu, Yufeng Huang, Youcheng Wang, Yancheng Dong, Sanbin Wang, Cheng Qian
Journal: Journal of Clinical Oncology (2023)

7553 Background: CD19 chimeric antigen receptor (CAR) T cell therapy has shown promising efficacy in the r/r B-NHL. However, many patients fail to respond, or quickly relapse after the initial response. To improve efficacy, we established a novel PrimeCAR platform (PRIMCAR) that shortens the manufacture time to about 2 days and enriches more stem cell-like memory T (T scm ) cells in the product. The MC-1-50 CAR-T cells produced by the PRIMCAR platform have exhibited a promising efficacy for B-ALL (Shiqi Li, et al. J Clin Oncol 2022; 40 [suppl 16]. Abstract 7008). Here, we report the preliminary safety and efficacy data of MC-1-50 for r/r B-NHL. Methods: In this Phase I /II study (NCT04271410), MC-1-50 CAR T cells were manufactured by the PRIMCAR platform. T cells were infected with a lentiviral vector encoding a humanized CD19 specific scFv following 4-1BB and CD3ζ cytoplasmic domain. Patients (pts) received single-dose of MC-1-50 at dose ranged 0.5-5×10 5 CAR+/kg (Level 1, 0.5×10 5 CAR+/kg; Level 2, 3×10 5 CAR+/kg; Level 3, 5×10 5 CAR+/kg). Pts were pre-conditioned with fludarabine (25-30 mg/m 2 ) and cyclophosphamide (200-300 mg/m 2 ) daily for 3 days. Toxicity was graded by CTCAE, CRS and ICANS were graded by ASTCT criteria. Primary endpoints are the dose-limiting toxicities (DLTs) rate in the first 28 d and safety to determine a recommended Phase II dose (RP2D). Results: As of May 2022, thirteen pts with r/r B-NHL were infused with MC-1-50. Disease characteristics and outcomes are shown in the table. No DLTs were reported. 3 pts (23.08%) experienced CRS, including 2 (15.38%) at grade 1, and 1 (7.69%) at grade 2, no ≥ 3 CRS were observed, and no ICANS occurred. A preliminary dose-dependent response was observed. At dose Level 1 (DL1), none of the 3 patients showed a good response. At DL2, two patients showed PR response, and 3 of the 5 patients achieved CR response. At DL3, 5 of 5 patients achieved CR response. These patients with CR response did not experience a relapse during the followed-up (ranging from 5-18 months). CAR-T expansion was observed in all dose levels, although long-term persistence cannot be evaluated yet, 4 of 5 patients in DL2 and 3 of 5 patients in DL3 had detectable CAR expression by qPCR (≥50 copy/ ug DNA) in the 6-month follow-up. Conclusions: The PRIMCAR platform could produce CAR T cells quickly with a high percentage of T scm . Treatment of r/r B-NHL at very low dose resulted in excellent safety profiles while exhibiting a high and durable efficacy. Clinical trial information: NCT04271410 . [Table: see text]
Incidence of second primary malignancies (SPMs) in patients with multiple myeloma (MM) receiving anti-CD38 monoclonal antibodies (mAbs): A systematic review and meta-analysis.
Authors: Agrima Mian, Syed Arsalan Ahmed Naqvi, Ahsan Ayaz, Muhammad Husnain, Mohammed A. Aljama, Ghulam Reham Mohyuddin, Kelly Koehn, Meera Mohan, Irbaz Bin Riaz, Rajshekhar Chakraborty
Journal: Journal of Clinical Oncology (2023)

e24078 Background: The addition of anti-CD38 mAbs, daratumumab and isatuximab, to standard anti-myeloma regimens have drawn scrutiny towards long-term safety concerns, including the risk of SPMs. ICARIA-MM study reported SPMs in 3.9% patients (pts.) in the Isatuximab, pomalidomide and dexamethasone (Isa-Pd) arm compared to 0.7% in the Pd arm. We hypothesized that exposure to anti-CD38 mAbs could potentially increase risk of SPMs due to prolonged immunosuppression. An assessment of this association is warranted, given the improved life expectancy and growing prevalence of pts. with MM. Methods: We performed a meta-analysis on data obtained from RCTs published between January 2005 and April 2022 that compared anti-CD38 mAb-based regimens to other standard anti-myeloma regimens (control) in pts. with newly diagnosed or relapsed/refractory (r/r) MM. Total number of SPMs (including categories) were extracted for pts. in both groups. Malignant melanomas were included under solid SPM category. Binary outcome data were analyzed using fixed-effect Peto method. Treatment effect estimates were expressed as odds ratio (OR) and 95% confidence interval (CI). I 2 &gt; 50% indicated substantial heterogeneity. Results: 10 RCTs involving 4980 pts. were included, with 2824 (57%) and 2156 (43%) pts. randomized to the anti-CD38 mAb and control arms, respectively (Table). Overall, 191 and 112 SPMs were reported in the anti-CD38 mAb and control arms, respectively. At a median follow-up of 35.3 months, anti-CD38 mAb exposure was associated with an increased risk of developing SPMs compared to control (6.8% vs. 5.2%; OR: 1.53 [95% CI: 1.20-1.95]; I 2 = 0%). Non-melanoma cutaneous cancers were the most common, and higher in the anti-CD38 mAb vs. control arms (92 versus 47; OR: 1.77 [95% CI: 1.25-2.51]; I 2 = 0%). The increase in solid cancers (including melanoma) (OR: 1.28 [95% CI: 0.85-1.95]) and hematologic SPMs (OR: 1.86; [95% CI: 0.81-4.27] was not significant. On sensitivity analysis, the total number of SPMs were higher in the anti-CD38 mAb arm vs. control arm, regardless of the presence of immunomodulatory drugs in combination regimen. Conclusions: This meta-analysis shows an increased risk of SPMs in pts. with MM exposed to daratumumab or isatuximab, particularly that of non-invasive cutaneous tumors. This association should be further investigated in real-world settings using large databases. [Table: see text]
Association of guideline adherence in diagnosis and treatment of pancreatic neuroendocrine tumors with survival.
Authors: Oliver Overheu, Doreen M. Gisder, Stefanie Noepel-Duennebacke, Anna-Lena Kraeft, Monika Janot-Matuschek, Waldemar Uhl, Andrea Tannapfel, Anke C. Reinacher-Schick
Journal: Journal of Clinical Oncology (2023)

e16241 Background: Clinical guidelines and their adherence are important instruments to ensure quality in diagnosis and treatment, especially when treating rare diseases like pancreatic neuroendocrine tumors (PanNET). However, data on guideline adherence and its impact on outcome in PanNET is limited. Methods: Cases of PanNET according to 2017 WHO definition at our university hospital between 2010 and 2019 were retrospectively identified. Adherence to ENETS guideline 2007/2012 and the German S2k guideline was evaluated among four categories (diagnostics: chromogranin A (CgA) testing, somatostatin receptor imaging, discussion in an interdisciplinary tumor board; pathology: reporting of grading, Ki67 and synaptophysin expression; surgical treatment; systemic treatment including aftercare). Guideline adherence within these categories was valued with one point per fulfilled criterion and a final score between 0-8 points was calculated. Data was analyzed using Student’s t-test, Chi-square test and Spearman’s correlation coefficient test. Results were considered significant at α = 0.05. Results: Overall, 115 patients (47% female) with a diagnosis of PanNET were identified. Mean age was 61 (±13.5) years. Mean overall survival (OS) was 45 months, mean recurrence free survival (RFS) was 47 months. During the study period 21 patients (18%) had died, 6 patients (5%) were lost-to-follow-up and 11 patients (10%) had a recurrent disease after initially curative resection. 24 patients (21%) presented with metastatic disease upon diagnosis. Guideline adherence concerning pathology reports (97%) as well as systemic (91%) and surgical treatment (75%) was high, while complete adherence in diagnostic modalities was low (5%). However, the latter was mainly driven by lack of CgA testing (31%), and somatostatin receptor imaging (11%) not being performed on initial diagnosis, but in most cases during follow-up. Subsequently, complete guideline adherence (8/8) across all categories was rare (3%). However, a higher overall score was associated with survival (p = 0.032, V = 0.321). Long term survivors had a higher mean overall adherence score (5.6 vs. 6.1; p = 0.05). In addition, the composite score of surgical and systemic therapy was significantly correlated with RFS (ρ = 0.254, p = 0.016). Conclusions: The quality in diagnosis and treatment of PanNET in our cohort was high. These are the first data to demonstrate a positive impact of guideline adherence on survival and RFS in PanNET.